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- PDB-7lfs: Crystal structure of the epidermal growth factor receptor extrace... -

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Basic information

Entry
Database: PDB / ID: 7lfs
TitleCrystal structure of the epidermal growth factor receptor extracellular region with A265V mutation in complex with epiregulin
Components
  • Isoform 4 of Epidermal growth factor receptor
  • Proepiregulin
KeywordsSIGNALING PROTEIN / receptor / epiregulin / glioblastoma / cancer / mutation / extracellular / asymmetric / dimer / ErbB1 / EGFR
Function / homology
Function and homology information


luteinizing hormone signaling pathway / ovarian cumulus expansion / ovulation / ERBB4-ERBB4 signaling pathway / negative regulation of smooth muscle cell differentiation / ERBB2-ERBB4 signaling pathway / primary follicle stage / female meiotic nuclear division / PI3K events in ERBB4 signaling / transmembrane receptor protein tyrosine kinase activator activity ...luteinizing hormone signaling pathway / ovarian cumulus expansion / ovulation / ERBB4-ERBB4 signaling pathway / negative regulation of smooth muscle cell differentiation / ERBB2-ERBB4 signaling pathway / primary follicle stage / female meiotic nuclear division / PI3K events in ERBB4 signaling / transmembrane receptor protein tyrosine kinase activator activity / positive regulation of innate immune response / mRNA transcription / oocyte maturation / positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / epidermal growth factor receptor binding / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / eyelid development in camera-type eye / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of cell division / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / keratinocyte proliferation / MAP kinase kinase kinase activity / SHC1 events in ERBB4 signaling / anatomical structure morphogenesis / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of protein kinase activity / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of bone resorption / embryonic placenta development / positive regulation of phosphorylation / salivary gland morphogenesis / Nuclear signaling by ERBB4 / peptidyl-tyrosine autophosphorylation / keratinocyte differentiation / positive regulation of peptidyl-serine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / positive regulation of mitotic nuclear division / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / basal plasma membrane / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / animal organ morphogenesis / Signal transduction by L1 / positive regulation of cytokine production / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation
Similarity search - Function
24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Alpha-Beta Horseshoe / Receptor L-domain / Furin-like cysteine-rich domain ...24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Alpha-Beta Horseshoe / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 1. / : / EGF-like domain signature 2. / EGF-like domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Alpha Beta
Similarity search - Domain/homology
Proepiregulin / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.5 Å
AuthorsHu, C. / Leche II, C.A. / Stayrook, S.E. / Ferguson, K.M. / Lemmon, M.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA198164 United States
CitationJournal: Nature / Year: 2022
Title: Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias.
Authors: Hu, C. / Leche 2nd, C.A. / Kiyatkin, A. / Yu, Z. / Stayrook, S.E. / Ferguson, K.M. / Lemmon, M.A.
History
DepositionJan 18, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 17, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 4 of Epidermal growth factor receptor
B: Isoform 4 of Epidermal growth factor receptor
C: Isoform 4 of Epidermal growth factor receptor
D: Isoform 4 of Epidermal growth factor receptor
E: Proepiregulin
F: Proepiregulin
G: Proepiregulin
H: Proepiregulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)253,03119
Polymers248,1228
Non-polymers4,90911
Water00
1
A: Isoform 4 of Epidermal growth factor receptor
E: Proepiregulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,0004
Polymers62,0312
Non-polymers9702
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4060 Å2
ΔGint4 kcal/mol
Surface area25120 Å2
MethodPISA
2
B: Isoform 4 of Epidermal growth factor receptor
F: Proepiregulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,3845
Polymers62,0312
Non-polymers1,3533
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4530 Å2
ΔGint9 kcal/mol
Surface area25970 Å2
MethodPISA
3
C: Isoform 4 of Epidermal growth factor receptor
G: Proepiregulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,4255
Polymers62,0312
Non-polymers1,3943
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4190 Å2
ΔGint6 kcal/mol
Surface area25790 Å2
MethodPISA
4
D: Isoform 4 of Epidermal growth factor receptor
H: Proepiregulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,2225
Polymers62,0312
Non-polymers1,1913
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3400 Å2
ΔGint6 kcal/mol
Surface area25320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.974, 201.331, 92.148
Angle α, β, γ (deg.)90.000, 99.040, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Protein/peptide , 2 types, 8 molecules ABCDEFGH

#1: Protein
Isoform 4 of Epidermal growth factor receptor / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 56550.254 Da / Num. of mol.: 4 / Mutation: A265V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Protein/peptide
Proepiregulin


Mass: 5480.307 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EREG / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: O14944

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Sugars , 4 types, 11 molecules

#3: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#4: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.75 Å3/Da / Density % sol: 55.26 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 8 mg/ml protein, 1% w/v tryptone, 1 mM sodium azide, 50 mM HEPES (pH 7.0), 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.03318 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 14, 2020 / Details: Undulator
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03318 Å / Relative weight: 1
ReflectionResolution: 3.5→100.666 Å / Num. obs: 35094 / % possible obs: 99.2 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 3.5 % / Biso Wilson estimate: 200 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.075 / Rpim(I) all: 0.048 / Rrim(I) all: 0.089 / Rsym value: 0.075 / Net I/av σ(I): 5 / Net I/σ(I): 8.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
3.5-3.693.61.2020.61788250290.7431.4161.2021.197.4
3.69-3.913.60.6771.11726248450.4210.7990.6772100
3.91-4.183.50.36421587645790.230.4310.3643.3100
4.18-4.523.30.1963.71414542490.1270.2340.1965.699.9
4.52-4.953.50.12261372639250.0770.1450.1228.599.9
4.95-5.533.70.1076.91320535830.0650.1260.1071099.9
5.53-6.393.60.0868.41119831110.0530.1010.08611.799.8
6.39-7.833.30.05712.2884826530.0370.0680.05716.299.4
7.83-11.073.20.03117.5640720240.020.0380.03125.697.8
11.07-48.0633.40.02814.6367710960.0180.0330.02837.395.2

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation8.14 Å44.38 Å
Translation8.14 Å44.38 Å

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Processing

Software
NameVersionClassification
PHENIXdev_3915refinement
XDS20200417data reduction
SCALA3.3.22data scaling
PHASER2.8.3phasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WB7

5wb7


Resolution: 3.5→44.38 Å / SU ML: 0.72 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 37.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.3148 1744 4.98 %0
Rwork0.2663 33286 --
obs0.2688 35030 99.16 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 226.37 Å2 / Biso mean: 99 Å2 / Biso min: 30 Å2
Refinement stepCycle: final / Resolution: 3.5→44.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16120 0 323 0 16443
Biso mean--158.53 --
Num. residues----2184
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.5-3.60.44491400.40282649278995
3.6-3.720.41371490.369427922941100
3.72-3.850.38181260.347628082934100
3.85-4.010.35761550.322827542909100
4.01-4.190.37081320.303228082940100
4.19-4.410.33731570.294227762933100
4.41-4.690.3261450.262427772922100
4.69-5.050.27631310.254928082939100
5.05-5.550.35761620.27627972959100
5.55-6.350.30681510.283327652916100
6.36-80.35821400.26862806294699
8-44.380.24831560.21212746290297

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